PROPHYLAXIS OF GENETICALLY-DETERMINED DIABETES BY DIAZOXIDE - A STUDYIN A RAT MODEL OF NATURALLY-OCCURRING OBESE DIABETES

The study was carried out using a new rat model of naturally occurring obese, nonketotic diabetes, Otsuka Long-Evans Tokushima Fatty rat (Ka wano et al., Diabetes 41: 1422-1428, 1992), which closely resembles ob ese noninsulin-dependent diabetes in human. At the age of 3.5 wk, body weight, glucose tolerance and plasma insulin level after glucose load were normal in Otsuka Long-Evans Tokushima Fatty rats, indicating the animals are at nonobese, prediabetic phase. At this age, however, glu cose-stimulated insulin release by pancreatic islets in vitro was abno rmally exaggerated whereas the islet insulin content and glucose metab olism by the islet cells were normal. Administration of diazoxide (0.2 % in diet), an inhibitor of insulin secretion, to Otsuka Long-Evans To kushima Fatty rats from the age of 4 to 12 wk completely prevented the development of obesity and insulin resistance, which was accompanied by marked improvement of glucose tolerance and disappearance of exagge rated B cell response to glucose in vitro. This is the first report of successful pharmacological prevention of genetically determined obese diabetes.